718. How evidence shapes implementation: beware the extrapolation fallacy

Abstract Background As psychedelic therapies advance toward regulatory approval worldwide, significant questions arise about the adequacy of traditional evidence hierarchies for evaluating these complex interventions. Psychedelic-assisted therapies combine pharmacological, psychological, contextual, and phenomenological elements that challenge conventional randomized controlled trial (RCT) designs. Traditional RCT-centric evidence frameworks may not adequately capture the multifaceted nature of these interventions, potentially limiting their appropriate evaluation for regulatory decision-making. The Independent Psychedelic Evidence Assessment Working Group (IPEA-WG) was established in August 2025 to critically examine existing frameworks and propose pluralistic approaches grounded in contemporary philosophy of evidence and causality in medicine. Aims & Objectives This study aims to improve the current framework for evaluation of psychedelic therapies given their unique characteristics as complex interventions. We hypothesize that evidential pluralism provides more robust assessment than RCT-centric hierarchies. The primary objective is to develop evidence-based recommendations for research designs, interpretation and regulatory decision-making that account for the contextual complexity and causal mechanisms underlying psychedelic therapies.

Method: IPEA-WG convenes multidisciplinary experts including philosophers, clinicians and regulatory scientists, with minimum conflicts of interest, to review evidence assessment frameworks for psychedelic interventions. We analyze regulatory guidelines, systematic reviews, and clinical trial designs through philosophical lenses including evidential pluralism, causal dispositionalism, and argumentation frameworks. The working group conducted eight keynote lectures featuring leading psychedelic experts across pharmacology, neuroimaging, clinical trials, causal inference, and indigenous perspectives, followed by a two-day in-person workshop for synthesis and consensus-building.

Results: The working group will identify key limitations in traditional evidence hierarchies when applied to psychedelic therapies, particularly regarding functional unblinding, psychotherapy and the integration of mechanistic evidence. Our analysis aims to reveal that pluralistic evidence frameworks better accommodate the complex causal pathways and contextual factors inherent in psychedelic-assisted therapies. We are developing and will present in June a comprehensive set of recommendations integrating diverse evidence types while maintaining scientific rigor. Discussion & Conclusions Traditional evidence hierarchies, while valuable for many pharmaceutical interventions, may inadequately assess psychedelic therapies due to their complex, multifaceted nature. Our work aims to support the adoption of pluralistic evidence frameworks that incorporate mechanistic reasoning, causal inference methods, and diverse evidence sources in addition to conventional RCTs. These frameworks provide more contextually appropriate and scientifically robust evaluation methods for regulatory decision-making. As regulatory decisions for psychedelic therapies loom globally, this work equips researchers, clinicians, and policymakers with conceptual tools for rigorous, contextually appropriate evidence evaluation. The IPEA-WG's recommendations will emphasize the need for flexible, philosophically informed approaches to evidence assessment that maintain scientific rigor while acknowledging the unique characteristics of psychedelic-assisted therapies as complex interventions.